Head and neck squamous cell cancer (HNSCC) is the sixth most common malignancy worldwide. It is twice as common in Veterans because of factors such as increased tobacco and alcohol use. Although some progress has been made in the prevention, diagnosis, and treatment of HNSCC, it continues to have a poor prognosis in most cases, and the typical course is associated with disfigurement, pain, and impaired function. Since cancer, including HNSCC, generally has been shown to be in part caused by the failure of the patient’s own immune system to attack and kill cancer cells, a recent new treatment strategy has been developed that is capable of arming the patient’s own T lymphocytes (a type of immune cell) to destroy the cancer. This new treatment is called immunotherapy. Unfortunately, although it is a very effective treatment for HNSCC, some patients do not respond to it or the disease worsens after an initial response (a phenomenon called resistance). This project studies the causes of resistance to immunotherapy in HNSCC. We hypothesize that immunotherapy, specifically in this case an antibody against PD1 (a protein expressed on the membrane of T lymphocytes), inhibits tumor growth by activating pathways that encourage immune cells to enter into the tumor and kill cancer cells. Resistance develops because, in some patients, these beneficial effects of immunotherapy do not take place and/or immunotherapy stimulates other mechanisms that suppress the ability of immune cells to function. The studies we are proposing will be conducted in blood and tumor samples from patients with HNSCC that have been treated with immunotherapy with the PD1 antibody. Because no experiments are done directly on patients, these studies will not pose a risk to patients. We will also perform experiments in mice to partially mimic conditions found in patients and in the cell culture dish to directly test the mechanisms that can only be studied in such a controlled setting. In mice, we will test whether combination therapies of the Food and Drug Administration-approved immunotherapeutic PD1 antibody with novel drugs that act on the pathways we are studying can be more beneficial in HNSCC than the PD1 antibody alone. Some of these drugs are already tested for use in humans. It is thus possible that our studies set the stage for clinical trials that, in 3-4 years, will test these new combination therapies. Ultimately, these studies will allow the understanding of why immunotherapy works in some people and why it doesn’t work in others. This information will help develop new therapies for HNSCC patients, thus improving their survival and quality of life. Furthermore, we anticipate that the results of our studies will have a broad application to many other cancers besides HNSCC. This research is relevant to the new fiscal year 2016 immunotherapy Peer Reviewed Cancer Research Program topic area. There is a strong reason why immunotherapy has been added as a topic area: it is an exciting, promising, and, indeed, “breakthrough” strategy for cancer treatment. Our research will provide a basic molecular understanding of how immunotherapy works or does not in some cases, allowing a strategy to maximize its efficacy. It is worth noting that Veterans often carry more medical conditions than the general population, making treatment sometimes difficult. However, immunotherapy has, in general, relatively mild side effects, unlike classic chemotherapy and radiation treatment. Thus, our studies could eventually lead to advancing the use of immunotherapy and provide treatments that further reduce the suffering of the patients and the stress of their families, especially in the Veteran and active military population.